The term "nitrogen control" describes the phenomenon whereby a limitation of the ammonia supply during growth of bacteria results in an increase in the synthesis of ammonia-assimilatory enzymes, some amino acid binding proteins, and some amino acid catabolic enzymes. Genetic studies with enterobacteria reveal that regulation via nitrogen availability is under the control of three regulatory loci: glnF, glnG, and glnL. Both positive and negative controls operate at the transcriptional level. GlnF codes for a specific sigma factor, whereas the product of glnL appears to mediate the interconversion of the glnG product, NR1, from repressor to positive activator in response to nutritional conditions. However, neither the biochemistry of NR1 activation nor the process by which the level of intracellular ammonia signals this interconversion is understood at present. For this reason, a study of the physiological parameters of the nitrogen control response was made in E. coli K12 using the level of glutamine synthetase (GS) as a measure of regulation. It was determined that addition of some D-amino acids to cells growing in medium containing excess ammonium nitrogen elicited an increase in the level of synthesis of GS. Because the rate of increase effected by a combination of D-glu, D-thr, D-lys and gly is equivalent to that which occurs when ammonia is exhausted, it was reasoned that these amino acids might participate, either directly or indirectly, in the generation of the specific metabolic signal for the nitrogen control response. When the distribution of the amino nitrogen from these amino acids, added to cells cultured in media containing isotopic nitrogen was examined by mass spectrometry, an increase in serine biosynthesis was observed. It was subsequently demonstrated that the increase in GS level elicited by the D-amino acids is dependent on the activity of serine hydroxymethyltransferase (SHMT). Further studies with inhibitors and mutants suggest that SHMT is involved in generating the putative metabolic signal which ultimately may be an early purine intermediate.